This invention was made in part with the assistance of grants from the Veterans Administration. The government has certain rights in this invention.
The alcohol sensitizing drugs disulfiram (tetraethylthiuram disulfide; Antabuse.RTM.) and carbimide (citrated calcium carbimide; Temposil.RTM.) increase blood acetaldehyde concentrations in the presence of ethanol by inhibiting the oxidation of acetaldehyde to acetic acid by aldehyde dehydrogenase (AlDH), thereby producing physiological effects that deter further drinking by alcoholics.
The absorption of calcium carbimide following oral administration is extremely rapid, causing nausea, headache and vomiting. In an attempt to reduce the rate of absorption, calcium carbimide is formulated as a slow release tablet, and to prevent its decomposition to ammonia, it is prepared in the citrated form (1 part drug to 2 parts citric acid). In the gastric juices, calcium carbimide is hydrolyzed to carbimide (cyanamide, H.sub.2 NCN) which is rapidly absorbed into the portal circulation. Data from animal experiments indicate that the drug is rapidly absorbed, metabolized and eliminated, and in view of the rapid onset and short duration of the calcium carbimide-ethanol reaction (CER), it is likely that absorption, metabolism and elimination are also rapid in humans. Cyanamide itself does not inhibit AlDH, but must be enzymatically activated by catalase to an as-yet unidentified active metabolite.
Disulfiram continues to be widely used in alcoholism treatment; however, there has been concern that its repeated use may induce toxicity. The use of calcium carbimide is not approved in the United States. In Canada and other countries, calcium carbimide has not been widely used because of its short duration of activity, which lasts approximately 24 hours. This is due to its facile conversion in vivo to an acetylated derivative, viz. acetylcyanamide (AC), which is rapidly excreted in the urine. At least 94% of the administered cyanamide is eliminated within 6 hours via this route by the rat. Like cyanamide, AC is devoid of AlDH inhibitory activity in vitro.
Therefore a continuing need exists for alcohol sensitizing and deterrent drugs which can substantially elevate blood acetaldehyde levels in the presence of ethanol for a prolonged period following oral administration.